Cellular and Molecular Mechanisms of the Pathogenesis of Aspirin Exacerbated Respiratory Disease

阿司匹林加重呼吸系统疾病发病机制的细胞和分子机制

• 批准号: 10443626
• 负责人: Whitney W Stevens
• 金额: $ 18.97万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443626
• 关键词: Address; Adrenal Cortex Hormones; Affect; Airway Disease; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Area; Aspirin; Asthma; Attention; Automobile Driving; Award; Basophils; Biological Products; CCL2 gene; Caring; Cells; Characteristics; Chemotaxis; Chronic; Clinic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Communities; Cyclooxygenase Inhibitors; Data; Diagnosis; Diagnostic; Disease; Disease Marker; Eicosatetraenoic Acids; Enzymes; Evaluation; Flow Cytometry; Growth; Hypersensitivity; Immune; Immunology; Impairment; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-5; K-Series Research Career Programs; Lead; Lipids; Mass Spectrum Analysis; Measures; Mediating; Mediator of activation protein; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Metabolism; Molecular; Morbidity - disease rate; Nasal Lavage Fluid; Nasal Polyps; Operative Surgical Procedures; Oral; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Play; Process; Protocols documentation; Quality of life; Reducing Agents; Research; Respiratory Disease; Role; Scientist; Severity of illness; Sinus; Solid; Source; Specimen; Step training; Testing; Therapeutic Agents; Tissues; Training; Triad Acrylic Resin; Universities; Work; airway inflammation; aspirin-exacerbated respiratory disease; asthmatic; career; career development; cell type; chronic rhinosinusitis; cohort; cyclooxygenase 1; cytokine; eosinophil; improved; innovation; interest; medical schools; new therapeutic target; novel; professor; radiological imaging; recruit; research study; socioeconomics; translational physician

ABSTRACT Dr. Whitney Stevens is a tenure-eligible Assistant Professor within the Division of Allergy and Immunology at the Northwestern University Feinberg School of Medicine. Her clinical and research interests focus on Aspirin Exacerbated Respiratory Disease (AERD), a disease consisting of the clinical triad of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma and sensitivity to inhibitors of the cyclooxygenase-1 enzyme. AERD is associated with significant morbidity, large socioeconomic burden, and negative impact on quality of life. Unfortunately, the underlying mechanisms of AERD pathogenesis are not well defined. As a result, current diagnostic and treatment options for affected patients remain limited, making AERD a large unmet clinical need. This career development award, under the mentorship of Dr. Robert Schleimer, focuses on investigating the cellular and molecular mechanisms of AERD pathogenesis to advance the understanding of this disease process. Dr. Stevens has preliminary evidence suggesting that basophils, as well as certain arachidonic acid metabolites, are elevated in nasal polyps of patients with AERD compared to patients with aspirin tolerant CRSwNP. The central hypothesis of the current proposal is that basophils and products of the 15-lipoxygenase pathway promote the exaggerated sinonasal inflammatory response and severe clinical characteristics observed in patients with AERD. This hypothesis will be addressed by 3 non-overlapping but complementary aims: 1) Correlation of the enhanced infiltration and activation of basophils with clinical disease severity in AERD; 2) Identification of the mechanisms responsible for the recruitment and activation of basophils in AERD nasal polyps; and 3) Examination and characterization of the effects of 15-lipoxygenase products in promoting the chronic inflammation observed in AERD nasal polyps. This study is innovative in that it will use novel recent data generated by Dr. Stevens to further investigate areas of AERD that are not currently well understood. This work will also lead to the expansion of what will become one of the largest clinically validated AERD cohorts available for study. Importantly, this award will provide Dr. Stevens with additional career development and training needed to build her own successful research team, establish independence from her mentor and significantly advance her career studying AERD pathogenesis.

抽象的 惠特尼·史蒂文斯 (Whitney Stevens) 博士是该大学过敏和免疫学系的终身助理教授 西北大学范伯格医学院。她的临床和研究兴趣集中在阿司匹林 急性呼吸系统疾病 (AERD)，一种由慢性鼻窦炎临床三联征组成的疾病 鼻息肉 (CRSwNP)、哮喘和对 cyclooxygenase-1 酶抑制剂的敏感性。 AERD 是 与显着的发病率、巨大的社会经济负担以及对生活质量的负面影响相关。 不幸的是，AERD 发病机制的根本机制尚未明确。结果，当前 受影响患者的诊断和治疗选择仍然有限，这使得 AERD 成为一个巨大的未满足的临床需求。 该职业发展奖在 Robert Schleimer 博士的指导下，重点调查 AERD 发病机制的细胞和分子机制，以促进对该疾病的了解 过程。史蒂文斯博士有初步证据表明嗜碱性粒细胞以及某些花生四烯酸 与阿司匹林耐受患者相比，AERD 患者鼻息肉中的代谢物升高 CRSwNP。当前提案的中心假设是嗜碱性粒细胞和 15-脂氧合酶的产物 途径促进夸张的鼻腔炎症反应和观察到的严重临床特征 患有 AERD 的患者。这一假设将通过 3 个不重叠但互补的目标来解决：1) AERD 中嗜碱性粒细胞浸润和活化增强与临床疾病严重程度的相关性； 2） 确定 AERD 鼻腔中嗜碱性粒细胞募集和激活的机制 息肉； 3) 15-脂氧合酶产品在促进 在 AERD 鼻息肉中观察到慢性炎症。 这项研究的创新之处在于它将利用史蒂文斯博士最近生成的新数据来进一步研究领域 目前尚未得到很好理解的 AERD。这项工作还将导致扩展 可用于研究的最大的经临床验证的 AERD 队列之一。重要的是，该奖项将为博士提供。 史蒂文斯需要额外的职业发展和培训来建立自己的成功研究团队， 建立独立于导师的地位，并显着推进她研究 AERD 发病机制的职业生涯。